PT1390372E - 1-oxa-3,9-diaza-spiro`5,5]undecan-2-ones derivatives and its use as antagonist of the neurikinin receptor - Google Patents

Description

1

DESCRIPTION OF THE DRAWINGS OF 1-OXA-3,9-DIAZA-ESPIRO [5,5] UNDECAN-2-ONAS AND THEIR USE IN TREATING ANURGONISTS OF THE NEURIQUININE RECEPTOR " The invention relates to compounds of general formula

wherein (R 1) n is independently in each case halogen, lower alkyl or lower alkoxy; . R 2 is hydrogen, lower alkyl, halo-lower alkyl, - (CH 2) m -OH, - (CH 2) m -NR 2, - (CH 2) m O-lower alkyl, - (CH 2) m -C (O) - NR 2, that is - (CH 2) m -heteroaryl having 6 members, optionally substituted with one or more lower alkoxy, - (CH 2) m - non-aromatic 5- or 6-membered heterocyclyl, optionally substituted with hydroxy or lower alkyl; R is hydrogen or lower alkyl and may be the same or different in the case of R2; 2 n is 0, 1, or 2; m is 1, 2, 3 or 4; and the pharmaceutically acceptable acid addition salts of these compounds.

The compounds of formula I and their salts are characterized as having valuable therapeutic properties. It has been surprisingly found that the compounds of the present invention are antagonists of the Neurokinin-1 receptor (NK-1, substance P). Substance P is a naturally occurring undecapeptide belonging to the tachykinin peptide family, the latter having the designation referred to because of its rapid contractile action on the extra vascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein coupled receptors.

Neuropeptide receptors for substance P (NK-1) are widely distributed throughout the mammalian nervous system (especially in the brain and spinal ganglia), the circulatory system, and peripheral tissues (especially the duodenum and jejunum ) and are involved in the regulation of a number of different biological processes.

The central and peripheral actions of substance P of mammalian tachykinins have been. . associated with many states of inflammation including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease, as well as mediating the vomiting reflex and modulating central nervous system (CNS) pathologies such as the disease of Parkinson's (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640-1645).

In " Tachykinin Receptor and .Tachykinin Receptor Antagonists ", J. Auton. Pharmacol., 13, 23-93, 1993, a review is presented on the data on the utility of tachykinin receptor antagonists in the treatment of pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, in the attenuation of morphine withdrawal, cardiovascular changes, edema, such as thermal injury edema, chronic inflammatory diseases such as rheumatoid arthritis, bronchial asthma / hyperreactivity, and other respiratory diseases including allergic rhinitis, inflammatory diseases of the digestive system including ulcerative colitis and Crohn's disease, ocular lesions and ocular inflammatory diseases.

In addition, antagonists of Neurokinin-1 receptor antagonists are being developed for the treatment of various physiological conditions associated with an excess or imbalance of tachykinins, in particular of substance P. Examples of states in which substance P has been implicated in central nervous system disorders such as anxiety, depression and psychosis (WO 95 / 16,679, WO 95 / 18,124 and WO 95 / 23,798).

Neurokinin-1 receptor antagonists are also useful for the treatment of nausea and vomiting induced by treatments.

In addition, in the New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999, the reduction of cis-platin induced vomiting by a selective neurokinin-1 receptor antagonist has been reported.

In addition, in US 5,972,938 a method has been described for treating a psychomelonological or psychosomatic pathology by administration of a tachykinin receptor, such as an NK-1 receptor antagonist. The utility of neurokinin-1 receptor antagonists for the treatment of certain forms of urinary incontinence. is also described in " Neuropeptides, 32 (1), 1-49, (1998) " and in Eur. J. Pharmacol., 383 (3), 297-303, (1999) ".

WO 97/11940 describes a series of spiro compounds as inhibitors of fibrinogen-dependent platelet aggregation for the treatment of thrombosis. In Eur. J. Med. Chem. Chimica Therapeutica, 1974, 9 (4), pp. 416-423 describes novel neuroleptic butyrophenones with a piperidine-spiro-5-tetrahydrooxazinone ring system, with a neuroleptic profile analogous to that of haloperidol. In addition, GB 2,131,021 discloses benzoxazine derivatives with antipsychotic properties.

The compounds of formula I may also be used in the form of their precursors. Examples are esters, N-oxides, phosphate esters, glycolamide esters, glyceryl-conjugates and the like. The precursors may enhance the advantages of the present compounds as regards their adsorption, their pharmacokinetics, the distribution and transport to the brain.

It has been reported that NK1 receptor antagonists also have a beneficial effect on the therapy of traumatic brain injury (oral description by Prof. Nimmo, International Tachykinin Conference 2000 in La Grande Motte, France, October 17-20, 2000 under Neurokinin-1 (NK-1) Receptor Antagonists Improve the Neurological Outcome Following Traumatic Brain Injury "(Authors: AJ Nimmo, CJ Bennett, X.Hu, I. Cernak, R. Vink)

The objects of the present invention are the compounds of formula I and their therapeutically acceptable salts, the preparation of the above-mentioned compounds, medicaments containing them as well as of their manufacture and the use of the above-mentioned compounds in the control or in the prevention of diseases, in particular diseases and disorders of the kind referred to above, or in the manufacture of the corresponding medicaments.

The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example in the treatment or prevention of certain depressive disorders or vomiting by the administration of NK-1 receptor antagonists. An important depressive episode has been defined as having a duration of at least two weeks during which most of the day and almost every day there is either a depressed temperament or loss of interest or pleasure in all, or almost all, activities.

The following definitions of the general terms used in the present specification apply regardless of whether the terms arise alone or in combination. with 1-4

As used herein, the term " lower alkyl " denotes a straight-chain or branched alkyl group containing from 1 to 7 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like. Preferred lower alkyl groups are groups of carbon atoms. The term " lower haloalkyl " denotes a lower alkyl group in which one or more hydrogen atoms are replaced by halogen The term " lower alkoxy " denotes groups in which the alkyl residues are attached by an oxygen atom. The term "6-membered heteroaryl" denotes groups such as triazinyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl. Triazinyl and pyridinyl groups are preferred. The term " heterocyclyl " aromatic 5- or 6-membered heterocyclic ring "denotes groups such as pyrrolidinyl, imidazolidinyl, tetrahydro-pyranyl, pyrazolidinyl, piperidyl, piperazinyl or morpholinyl. of pharmaceutically acceptable acids " includes salts with inorganic acids and with organic acids such as acid hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like. Examples of preferred compounds of formula 1 are those in which R 2 is hydrogen, for example the following compounds: (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5- (3-chloro-phenyl) ) -l-oxa-3,9-diazaspiro [5.5] undecan-2-one, (5aS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5- (3,4-difluoro-phenyl) ) -l-oxa-3,9-diazaspiro [5.5] undecan-2-one, (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5- (3,4-dichloro-phenyl) - 1-oxa-3,9-diazaspiro [5.5] undecan-2-one (5RS) -9- (3,5-bis-trifluoromethylbenzoyl) -5-phenyl- spiro [5.5] undecan-2-one, (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5- (2,3-difluoro-phenyl) -1-oxa-3,9-diazaspiro [ 5,5] undecan-2-one, and (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5- (2,5-difluoro-phenyl) -1-oxa-3,9-diazaspiro [5.5 ] undecan-2-one. Also preferred are compounds of formula I in which R 2 is a 6-membered (CH 2) m -heteroaryl group, optionally substituted with one or more lower alkoxy. Examples of such compounds are 9- (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5-phenyl-3-pyridin-3-ylmethyl-1-oxa-3,9- (3,5-bis-trifluoromethyl-benzoyl) -3- (4,6-dimethoxy- [1,3,5] triazin-2-one (5RS) -9- yl) -5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2-one. Also preferred are. compounds of formula I in which R2 is - (CH2) m C (O) -N (CH3) 2. An example of such compounds is: (5RS) -2- [9- (3,5-bis- benzoyl) -2-chloro-5-phenyl-1-oxa-3,9-diazaspiro [5.5] undec-3-yl] -N, N-dimethylacetamide. Also preferred are compounds of formula I, in which R 2 is - (CH 2) m -OH. Examples of such compounds are: (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-hydroxy-propyl) -5-phenyl-1-oxa-3,9-diaza-spiro [ 5.5-undecan-2-one and (5RS) -9- (3,5-bis-trifluoromethylbenzoyl) -3- (2-hydroxyethyl) -5-phenyl-1-oxa-3,9-diazaspiro [ 5.5] undecan-2-one. Also preferred are those compounds of the formula wherein R 2 is a non-aromatic - (CH 2) m -heterocyclyl group, optionally substituted with hydroxy or lower alkyl. Examples of such compounds are: (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -3- (1-methyl-piperidin-4-yl) -5-phenyl-1-oxa- (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5-phenyl-3- (3-pyrrolidin-1-yl-propyl) -piperazin- oxo-3,9-diaza-spiro [5.5] undecan-2-one, (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-morpholin-4-yl-propyl) ) -5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2-one, (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -3- [3- 3-hydroxy-pyrrolidin-1-yl) -propyl] -5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2-one and (5RS) -9- (3,5-2is trifluoromethylbenzoyl) -3- (2-morpholin-4-yl-ethyl) -5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2-one. Also preferred are compounds of formula I, in which R 2 is - (CH 2) m -NR 2 -. (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-dimethylamino-4-yl-propyl) -5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2-one and 11 (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-dimethylaminoethyl) -5-phenyl-1-oxa- diaza-spiro [5.5] undecan-2-one.

The present compounds of formula X and their pharmaceutically acceptable salts can be prepared by methods which are known in the art, for example by the processes described below, which processes include: a) cyclizing a compound having the formula formula

CF, to a compound of formula

CF 3a wherein R 1 has the meanings given above, or b) reacting a compound of formula 12

with

R2-X to give a compound of formula

in which R 1 and R 2 have the meanings ascribed to them above and X is halogen, or c) reacting a compound of formula

to a compound of formula 13

CF, Ib wherein m and R 1 have been described above, or d) reacting a compound of formula

CF 3, b with a compound of formula

R2NH to a compound of formula

CF, Ib wherein the definition of R 1 is shown above, and R is hydrogen or lower alkyl, or formula e) reacting a compound with

to a compound of formula

in which R 1 is as described above and R 2 'and R 2' are independently of one another hydrogen, alkyl, aryl, heteroaryl or, taken together, form a non-aromatic carbocyclic or heterocyclic ring optionally substituted with halogen, hydroxy, lower alkoxy or hydroxyl or lower alkyl, and, if desired, converting the obtained compound into a pharmaceutically acceptable acid addition salt thereof. The following scheme and the specific examples 1 to 30 describe the processes for the preparation of compounds of formula I in more detail. The starting materials are known compounds and may be prepared according to methods known in the art. 15

1 H-NMR (CDCl3): Î'= 1.21â € ²-Carfoonyl-diimidazole MsCl = methanesulfonyl chloride â € ƒâ € ƒâ € ƒR1 CF3

1) MsCI / NElj ZJRjNH

are aryl, wherein in this scheme R2 'and R2 " independently of one another, hydrogen, alkyl, heteroaryl, or taken together form a non-aromatic carbocyclic or heterocyclic, optionally substituted with halogen, hydroxy, lower alkoxy, hydroxyl or lower alkyl.

According to the above scheme, a compound of formula IV is treated with n-butyllithium in tetrahydrofuran at -78 ° C for 30 minutes and then compound V is added and the mixture is stirred for 4 hours at -78Â ° C. The crude product obtained after isolation work in the presence of Pt.sub.2 in acetic acid at 2.7 bar is hydrogena. Obtained. the desired compound of formula II without purification in moderate to good yields.

A compound of formula II is cyclized to give a compound of formula Ia. The reaction is carried out in a solvent such as tetrahydrofuran in the presence of 1,1'-carbonyl-diimidazole: Stir the reaction mixture at room temperature for about 18 hours. The expected product was obtained after purification in good yields.

The compound of formula Ia is deprotonated with NaH (55% sodium hydride in mineral oil) at room temperature in dimethylformamide, dimethoxyethane. or N-methylpyrrolidine for 15 minutes, and an alkylating reagent is added. The reaction mixture is stirred at ambient temperature or at 80 ° C or at 100 ° C overnight. The desired compound of formula I is obtained after purification by column chromatography. 17

A compound of formula I (R2 = Me3 SiO (CH2) m-i-CH2) is deprotected under acidic conditions to provide a compound of formula Ib without purification.

According to example 23, a compound of formula Ib is treated with methanesulfonyl chloride in dichloromethane at 0 ° C in the presence of triethylamine for 90 minutes. After isolation, the methanesulfonate is dissolved. intermediate in dimethylformamide and sodium hydrogencarbonate, and an amine is added. The reaction mixture is stirred at room temperature overnight. The expected product of formula Ic is obtained after. purification by column chromatography. The salt formation is carried out at ambient temperature according to methods which are known. Process 12b) describes the reductive amination of a compound of formula II with a ketone, to a compound of formula III. The reaction is conducted in the presence of sodium triacetoxyborohydride e. of acetic acid. The reaction mixture is stirred at room temperature overnight. The desired product is used directly in the next step, without purification.

A compound of formula III is cyclized in a solvent such as tetrahydrofuran in the presence of 1,1'-carbonyl-diimidazole to give a compound of formula Id. The reaction mixture is stirred at ambient temperature for about 18 hours. After purification, the desired product was obtained in good yields. The process for the preparation of compounds of formula I, described in scheme 1, is novel. The preparation of similar compounds has been described in Eur. J. Med. Chem. -Chim. The R. (1974), 9 (4), 416-23 as follows:

After debenzylation, a reaction with (CF 3) 2 C 6 H 3 -C (O) Cl leads to compounds of formula I present. The salt formation is carried out at ambient temperature according to methods which are known per se and which are known to any person skilled in the art. Salts are considered not only with inorganic acids but also salts with organic acids. Examples of these salts are hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succihates, methanesulphonates, p-toluenesulphonates and others are examples of these salts. 19

As mentioned above, the compounds of formula I and their pharmaceutically usable addition salts have valuable pharmacological properties. The compounds of the present invention have been found to be Neurokinin-1 receptor antagonists (NK-1, substance P) -

Compounds were investigated according to the tests described hereinafter. The affinity for the NK1 receptor with human NK1 receptors in CHO cells infected with the human ΝΚχ receptor (using the Semliki virus expression system) was evaluated and radioactively labeled with [3 H] substance P (final concentration 0, 6 nM). The binding assays were carried out in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04%), leupeptin (8 pg / ml), MnCl2 (3 mM) and phosphoramidon (2 μΜ). Binding tests consisted of 250 μl of membrane suspension (1.25 x 105 cells / assay tube), 0.125 μl of replacement agent buffer and 125 μΐ of [3H] substance P. The replacement curves were determined at least seven compound concentrations. The test tubes were incubated for 60 minutes at room temperature, at which time the contents of the tubes were rapidly vacuum filtered through GF / C filters previously wet for 60 minutes with PEI (0.3%) with 2 x 2 mL of washes with HEPES buffer (50 mM, pH 7.4). Radioactivity retained on the filters was measured by scintillation counting. All tests were carried out in triplicate in at least 2 separate experiments. The affinity for the N.K-1 receptor, listed as pKi, is within the range of 7., 50-8.80 for the compounds of formula I of the present invention.

Example-No. [Example-No. pKi | 1 '18.29 | 16 8.21 -1 2 18.7 7 IIT 7.88 1 3 (8.58 18 7.81 | 4! 8.29 19 7.72 5 j-8.07 20 7.51, 6 _____ | s, 01 21 8.17 (Cififloxy); * 7 17.97 22 7.80. . Ι 8 1-7.96 23 8.47 I 9 '' 7.90 (k k k k k k k k k k k k k k k k k k k k k k k k k k k k k [ 9 | 12 S 8.41 27 8.20 | 13 1 (7.72 28 8.13 | 14 4B, 18 299, 98, U-16, 17, 15,

The compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations may be administered by the oral route, for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. Administration may, however, also be effected rectally, for example by assuming the form of suppositories, or parenterally, for example in the form of injectable solutions.

The compounds of formula I as well as their pharmaceutically usable acid addition salts can be processed together with pharmaceutically, inorganic or organic inert excipients, for the production of tablets, coated tablets, dragees and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc., may be used as such excipients, for example for tablets, coated tablets, dragees and hard gelatin capsules. Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, semi-solid and liquid polyols, etc. Suitable excipients for the manufacture of solutions and syrups, for example water, polyols, sucrose, invert sugar, glucose, and the like. Suitable excipients are for injectable solutions, for example water, alcohols, polyols, glycerol, vegetable oils, etc. Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid and liquid polyols, etc. 22

In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, osmotic pressure-varying salts, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances. The dosage may vary within wide limits and be, of course, adapted to the individual needs in each case. private. In general, in the case of oral administration, a daily dosage of between about 10 and 100 mg per person of a compound of general formula I should be suitable, although the above upper limit may also be exceeded when such necessary.

The following Examples illustrate the present invention without limiting it. All temperatures are given in degrees Celsius.

Example 1 (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5- (3-chloro-phenyl) -1-oxa-3,9-diazaspiro [5.5] undecan-2-one (RS) - {4- [2-Amino-1- (3-chloro-phenyl) -ethyl] -4-hydroxy-piperidin-1-yl} - (3,5-bis-trifluoromethyl-phenyl) -methanone

To a solution of 3.392 g (10 mmol) of 3-chlorobenzyl cyanide in tetrahydrofuran, cooled at -78 ° C, 6.25 ml (10 mmol) of n-butyl lithium in n-hexane (1.6 M). The solution was stirred for 30 minutes and 1- (3,5-bis-trifluoromethyl-benzoyl) -piperidin-4-one in tetrahydrofuran was added dropwise to the reaction mixture maintaining the temperature below -70 ° C. After stirring at -78 ° C for 4 hours, the reaction mixture was poured into an ice / saturated aqueous NH 4 Cl solution and extracted. with ethyl acetate. The organic phase was dried (MgSO 4) and concentrated under reduced pressure.

The crude material was dissolved in acetic acid and hydrogenated in the presence of PtC> 2 at 2.7 bar. The catalyst was filtered off, water and hydrochloric acid (1M) were added and the solution was extracted twice with dichloromethane. The aqueous phase was basified with concentrated sodium hydroxide and extracted twice with dichloromethane. The combined organic phases were dried and concentrated to give 2.21 g (46%) of the title compound. MS m / e (%): 495.1 (M + H +, 100). b) (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5- (3-chloro-phenyl) -1-oxa-3,9-diazaspiro [5.5] undecan-2-one (2-amino-1- (3-chloro-phenyl) -ethyl] -4-hydroxypiperidin-1-yl} - (3,5- bis-trifluoromethyl-phenyl) -methanone in 30 mL of tetrahydrofuran, 1.46 g (9 mmol) of 1,1'-carbonyl-diimidazole was added and the mixture was stirred overnight at room temperature in atmosphere. Water (15 mL) was added, the organic phase was separated, washed twice with hydrochloric acid solution (1 M), dried and evaporated. The residue was purified by flash column chromatography (SiO2, ethyl acetate) to provide 1.08 g (69%) of the title compound. MS m / e (%): 521.0 (M + H +, 100).

Example 2 (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5- (3,4-difluoro-phenyl) -1-oxa-3,9-diazaspiro [5.5] undecan-2-one

The title compound was obtained in comparable yields following the procedures described for example 1, starting from 3,4-difluorobenzyl cyanide instead of 3-chlorobenzyl cyanide in step a). MS m / e (%): 523.1 (M + H +, 100). . Example 3. (5 JRS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5- (3,4-dichloro-phenyl) -1-oxa-3,9-diazaspiro [5.5] undecan-2-one

The title compound was obtained in comparable yields following the procedures described for example 1, starting from 3,4-dichlorobenzyl cyanide instead of 3-chlorobenzyl cyanide in step a). MS m / e (%): 555, G (M + H +, 100), 557.0 (M + H +, 60).

Example 4 (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2-one

The title compound was obtained in comparable yields following the procedures described for example 1, starting from benzyl cyanide instead of 3-chlorobenzyl cyanide in step a). MS m / e (%): 487.2 (K + H +, 100).

Example 5 (5α-S) -9- (3,5-bis-trifluoromethyl-benzoyl) -5- (2,3-difluoro-phenyl) -1-oxa-3,9-diazaspiro [5.5] undecan-2 -one

The title compound was obtained in comparable yields following the procedures described for example 1, starting from 2,3-difluorobenzyl cyanide instead of 3-chlorobenzyl cyanide in step a). MS m / e (%): 523.1 (M + H +, 100). 26

Example 6 (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5- (2,5-difluoro-phenyl) -1-oxa-3,9-diazaspiro [5.5] undecan-2-one

The title compound was obtained in comparable yields following the procedures described for example 1, starting from 2,5-difluorobenzyl cyanide instead of 3-chlorobenzyl cyanide in step a) MS m / e (%): 0 (F 2 C 6 H 3 CH = CH 2, 100); 522.1 (M +, 3).

Example 7 (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5-o-toluoyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2-one

The title compound was obtained in comparable yields following the procedures described for example 1, starting from 2-methylbenzyl cyanide instead of 3-chlorobenzyl cyanide in step a). MS m / e (%): 118.1 (CH 3 C 6 H 4 CH = CH 2, 100); 501.2 (M + H +, 2).

Example 8 (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5- (4-chloro-phenyl) -1-oxa-3,9-diazaspiro [5.5] undecan-2-one 27

The title compound was obtained in comparable yields following the procedures described for example 1, starting from 4-chlorobenzyl cyanide instead of 3-chlorobenzyl cyanide in step a). MS m / e (%): 138.0 (C 1 -C 6 H 4 CH = CH 2, 100); 520.1 (M +, 3).

Example 9 (5 S) -9- (3,5-bis-trifluoromethyl-benzoyl) -5- (3,4-dimethyl-phenyl) -1-oxa-3,9-diazaspiro [5.5] undecan-2-

The title compound was obtained in comparable yields following the procedures described for example 1, starting from 3,4-dimethylbenzyl cyanide instead of 3-chlorobenzyl cyanide in step a). MS m / e (%): 515.2 (M + H +, 100).

Example 10 (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5- (3-methoxy-phenyl) -1-oxa-3,9-diazaspiro [5.5] undecan-2-one

The title compound was obtained in comparable yields following the procedures described for example 1, starting from 3-methoxybenzyl cyanide instead of 3-chlorobenzyl cyanide in step a). MS m / e (%): 134.1 (CH 2 OC 6 H 4 CH = CH 2, 100); 516.2 (M +, 3).

Example 11 (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5 '- (2-chloro-phenyl) -1-oxa-3,9-diazaspiro [5.5] undecan-2-one

The title compound was obtained in comparable yields following the procedures described for example 1, starting from 2-chlorobenzyl cyanide instead of 3-chlorobenzyl cyanide in step a). MS m / e (%): 521.1 (M + H +, 100).

Example 12 (5RS) -9- (3,5-Bis-trifluoromethyl-benzoyl) -3- (1-methyl-piperidin-4-yl) -5-phenyl-1-oxa-3,9-diaza-spiro [ (RS) - {[4- (2-Amino-1-phenyl-ethyl) -4-hydroxypiperidin-1-yl] - (3,5-bis-trifluoromethyl- phenyl) -methanone

To a solution of 1.69 g (5 mmol) of benzyl cyanide in tetrahydrofuran, cooled to -78 ° C under argon was added 3.75 ml (5 mmol) n-butyllithium hexane (1.6 M). The solution was stirred for 30 minutes and 1- (3,5-bis-trifluoromethyl-benzoyl) -piperidin-4-one in tetrahydrofuran was added dropwise to the reaction mixture, keeping the temperature below -70 ° C . After stirring at -78 ° C for 2 hours, the reaction mixture was poured into a mixture of ice and saturated aqueous NH 4 Cl and extracted with dichloromethane. The aqueous layer was dried (MgSO4) and concentrated under reduced pressure.

The crude material was dissolved in acetic acid and hydrogenated in the presence of PtC> 2 at 2.7 bar. The catalyst was filtered off, water and hydrochloric acid (1M) e. the solution was extracted twice with dichloromethane. The aqueous phase was basified with concentrated sodium hydroxide and extracted twice with dichloromethane. The combined organic layers were dried and evaporated. The residue was purified by column chromatography (SiO2, dichloromethane / methanol = 90:10) to give 0.73 g (34%) of the title compound MS m / e (%): 461.2 (M + H +, 100) b) (5S) - {9- (3,5-bis-trifluoromethyl-benzoyl) -3- (1-methyl-piperidin-4-yl) -5-phenyl-1-oxa- 9-diaza-spiro [5.5] undecan-2-one

To a solution of 4- [2-amino-1-phenyl-ethyl) -4-hydroxy-piperidin-1-yl] - (3,5-bis-trifluoromethyl- 1-yl) -methanone and 113 mg (1 mmol) of 1-methyl-4-piperidone in 1 mL of tetrahydrofuran, 0.114 mL (2 mmol) of acetic acid and 295 mg (1.4 mmol) of sodium triacetoxyborohydride were added. The reaction mixture was stirred overnight at room temperature. Saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the solution was extracted three times with dichloromethane. The combined organic layers were dried and evaporated under reduced pressure. Dissolved. the residue in 9 mL of tetrahydrofuran and 462 mg (2.85 mmol) of 1,1'-carbonyl-diimidazole. The mixture was stirred under argon at room temperature overnight and at 60 ° C for three days. After cooling, water (5 mL) was added, and the solution was extracted three times with dichloromethane. The combined organic layers were dried and evaporated. The residue was purified by column chromatography (SiO2, dichloromethane / methanol = 90:10) to give 388 mg (66%) of the title compound. MS m / e (%): 583.1 (M + H + , 100).

Example 13 (5RS) -9- (3,5-Bis-trifluoromethyl-benzoyl) -5-phenyl-3- (tetrahydro-pyran-4-yl) -1-oxa-3,9-diazaspiro [5.5] undecan-2-one

The title compound was obtained in comparable yields following the procedures described for example 12, starting from tetrahydro-4H-pyran-4-one instead of 1-methyl-4-piperidone in step b). MS m / e (%): 241.0 ((CF3) 2 C6 H3 CHO, 100); 570.0 (M +, 2). 31

Example 14 (5RS) -2- [9- (3,5-Bis-trifluoromethyl-benzoyl) -2-oxo-5-phenyl-1-oxa-3,9-diazaspiro [5.5] undec-3-yl] - N, N-dimethylacetamide

T

To a solution of 243 mg (0.5 mmol) of 9- (3,5-bis-trifluoromethyl-benzoyl) -5-phenyl-1-oxa-3,9-diaza-spiro [5: 5] 2-one in dimethylformamide, 24.0 mg (0.5 mmol) of a 55% suspension of sodium hydride in mineral oil at room temperature under argon. After 15 minutes, 12 6 mg (0.8 mmol) of 2-chloro-Î ±, Î ± -dimethylacetamide were added. The reaction mixture was stirred at 80 ° C. under argon from one day to the next. After the solvent was evaporated in vacuo, water (1 mL) was added, and the mixture was extracted twice with ethyl acetate. The organic phase was dried over Na2 SO4 and concentrated. The residue was purified by column chromatography (SiO2, Hexane / ethyl acetate = 1: 1) to provide 154 mg (54%) of the title compound. . MS m / e (%): 572.1 (M + H +, 100).

Example 15 (5αS) -9- (3,5-bis-trifluoromethyl-benzoyl) -3- (2,2-difluoro-ethyl) -5- (3,4-difluoro-phenyl) -1- 3,9-diazaspiro [ 5] undecan-2-one

To a solution of 261 mg (0.5 mmol) of 9- (3,5-bis-trifluoromethyl-benzoyl) -5- (3,4-difluorophenyl) -1-oxa-3,9 -diaza-spiro [5.5] undecan-2-one in dimethylformamide, 24 mg (0.5 mmol) of a 55% suspension of sodium hydride in mineral oil at room temperature under argon. After 15 minutes, 80 mg (0.55 mmol) of 2-bromo-1,1-difluoroethane was added. The reaction mixture was stirred at room temperature and under argon overnight. After the solvent was evaporated in vacuo, water (1 mL), and the mixture was extracted with ethyl acetate. The organic phase was dried over (Na2SO4) and concentrated. The residue was purified by flash chromatography (SiO 2, Hexane / ethyl acetate = 1: 1) to give 96 mg (33%) of the title compound. MS m / e (%): 587.1 (M + H +, 100).

Example 16 (5 (S) -9- (3,5-Bis-trifluoromethyl-benzoyl) -5-phenyl-3-pyridin-3-ylmethyl-1-oxa-3,9-diaza-spiro [5.5] undecan- 2-one

The title compound was obtained in comparable yields following the procedures described for example 15, starting from 3- (chloromethyl) pyridine hydrochloride instead of 2-bromo-1,1-difluoroethane and 9- (3,5- bis-trifluoromethyl-benzoyl) -5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2-one instead of 9- (3,5-bis-trifluoromethyl-benzoyl) -5- - (3,4-difluoro-phenyl) -1-oxa-3,9-diaza-spiro [5 '. 5] undecan-2-one. MS m / e (%): 578ml, (M + H +, 100).

Example 17 (5RS) -9- (3,5-Bis-trifluoromethyl-benzoyl) -3- (4,6-dimethoxy- [1,3,5] triazin-2-yl) -5- oxa-3,9-diaza-spiro [5.5] undecan-2-one

The title compound was obtained in comparable yields following the procedures described for example 15, starting from 2-chloro-4,6-dimethoxy-1,3,5-triazine in place of 2-bromo-1,1-difluoroethane , 9- (3,5-bis-trifluoromethyl-benzoyl) -5-phenyl-1-oxa-3,9-diazaspiro [5.5] undecan-2-one instead of 9- (3,5-bis-trifluoromethyl) benzoyl) -5- (3,4-difluorophenyl) -1-oxa-3,9-diaza-spiro [5.5] undecan-2-one and dimethoxyethane in place of dimethylformamide. MS m / e (%): 626.1 (M + H +, 100).

Example 18 (5αS) -9- (3,5-bis-trifluoromethyl-benzoyl) -3-methyl-5-phenyl-1-oxa-3,9-diazaspiro [5.5] undecan-2-one

The title compound was obtained in comparable yields following the procedures described for example 15, starting from methyl iodide instead of 2-bromo-1,1-difluoroethane, 9- (3,5-bis-trifluoromethyl) benzoyl) -5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2-one instead of 9- (3,5-bis-trifluoromethylbenzoyl) -5- 4-difluoro-phenyl) -1-oxa-3,9-diazaspiro [5.5] undecan-2-one and N-methylpyrrolidone instead of dimethylformamide. MS m / e (%): 241.0 ((CF3) 2 C6 H3 CHO, 100); 500, 1 (M +, 7).

Example 19 (5RS) -9- (3,5-Bis-trifluoromethyl-benzoyl) -5- (3,4-difluoro-phenyl) -3- (2-methoxy-ethyl) -1-oxa-3,9- diazaespiro [5. 5] undecan-2-one

The title compound was obtained in comparable yields following the procedures described for example 15, starting from 2-bromoethyl methyl ether instead of 2-bromo-1,1-difluoroethane. MS m / e (%): 581.0 (M + H +, 100).

Example 20 (5α, 5) -9- (3,5-bis-trifluoromethylbenzoyl) -5- (3,4-difluoro-phenyl) -3-methyl-1-oxa-3,9- spiro [5.5] undecan-2-one

The title compound was obtained in comparable yields following the extracts. procedures described for example 15 starting from methyl iodide instead of 2-bromo-1,1-difluoroethane. MS m / e (%): 537.2 (M + H +, 100).

Example 21 (S-RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-hydroxypropyl) -5-phenyl-1-oxa-3,9-diaza- 5.5] undecan-2-one

To a solution of 2.43 g. (5 mmol) of 9- (3,5-bis-trifluoromethyl-benzoyl) -5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2-one in N-methylpyrrolidone, 0.436 g ( 0.5 mmol) of a 55% suspension of sodium hydride in mineral oil at room temperature under argon. After 15 minutes, 1.27 g (5 mmol) of (3-bromopropoxy) -tert-butyldimethylsilane were added. The reaction mixture was stirred at 100 ° C under argon overnight. After cooling, a saturated aqueous NaHCO 3 solution was added and the mixture was extracted twice with ethyl acetate. The organic phase was dried over (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2, Hexane / ethyl acetate = 2: 1) to give 1.66 g (50%) of a yellow oil.

The oil was dissolved in a mixture. of hydrochloric acid with ethanol and the solution was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue taken up in dichloromethane and water. The organic phase was then washed twice with saturated aqueous NaHCO 3 solution. The organic phase was dried over MgSO 4 and evaporated. The residue was purified. by column chromatography (SiO 2 / ethyl acetate) to provide 0.83 g (30%) of the title compound. MS m / e (%): 545.2 (M + H +, 100).

Example 22 (5.RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-hydroxy-ethyl) -5-phenyl-1-oxa-3,9-diazaspiro [5.5 ] undecan-2-one

To a solution of 2.43 g (5 mmol) 9- (3,5-bis-trifluoromethyl-benzoyl) -5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2 -one in dimethylformamide, 0.436 g (0.5 mmol) of a 55% suspension of sodium hydride in mineral oil at room temperature under argon. After 30 minutes, (3-bromoethoxy) -tert-butyldimethylsilane (1.32 g, 5.5 mmol) was added. The mixture was stirred at room temperature under argon overnight. After the solvent was evaporated, a saturated aqueous NaHCO3 solution was added and the solution was extracted with ethyl acetate. The organic phase was dried over (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2, Hexane / ethyl acetate = 2: 1) to give 0.483 g (15%) of a white foam, which was dissolved in a mixture of hydrochloric acid / ethanol and stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue taken up in dichloromethane and water. The organic phase was washed twice with a saturated aqueous solution of NaHC03. The organic phase was dried over MgSO4 and evaporated to give 0.395 g (15%) of the title compound. MS m / e (%): 531.2 (M + H +, 100).

Example 23 (5RS) -9- (3,5-Bis-trifluoromethyl-benzoyl) -5-phenyl-3- (3-pyrrolidin-1-yl-propyl) -1-oxa-3,9-diaza-spiro [ 5.5] undecan-2-one

To a solution of 8-10 mg (1.49 mmol) of 9- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-hydroxypropyl) -5-phenyl-1-oxa-3,9 (5.5 ml) undecan-2-one in dichloromethane (15 ml), 301 mg (2.98 mmol) of triethylamine were stirred at room temperature under argon. After cooling to 0 ° C, 187 mg (1.64 mmol) of methanesulfonyl chloride was added and the reaction mixture was stirred under argon for 90 minutes. Water was added and the organic phase was separated, dried (Na 2 SO 4) and concentrated to provide 904 mg (98%) of a white foam. This foam was dissolved in dimethylformamide, and 243 mg of sodium hydrogen carbonate (2.9 mmol) and pyrrolidine (155 mg, 2.18 mmol) were added. The reaction mixture was stirred overnight at room temperature. After the solvent was evaporated, the residue was partitioned between water and ethyl acetate. The two phases were separated and the organic phase was dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO 2 / dichloromethane / methanol 97: 3) to provide 239 mg (27%) of the title compound. MS m / e (%): 598.0 (M + H +, 100).

Example 24 (5S) -9- (3,5-Bis-trifluoromethyl-benzoyl) -3- (3-morpholin-4-yl-propyl) -5-phenyl-1-oxa-3,9-diaza-spiro [ 5.5] undecan-2-one

The title compound was obtained in comparable yields following the procedures described for example 23, starting from morpholine instead of pyrrolidine. MS m / e (%): 614.2 (M + H + 100). .

Example 25 (5RS) -9- (3,5-Bis-trifluoromethyl-benzoyl) -3- (3-dimethylamino-4-yl-propyl) -5-phenyl-1-oxa-3,9- spiro [5.5] undecan-2-one

The title compound was obtained in comparable yields following the procedures described for example 23, starting from dimethylamine instead of pyrrolidine. MS m / e (%): 572.2 (M + H +, 100). 39

Example 26 (5.RS) -9- (3,5-Bis-trifluoromethyl-benzoyl) -3- [3- (3-hydroxy-pyrrolidin-1-yl) -propyl] -5-phenyl-1-oxa- 3,9-diaza-spiro [5.5] undecan-2-one

The title compound was obtained in comparable yields following the procedures described for example 23, starting from (R) -3-hydroxypyrrolidine instead of pyrrolidine. MS m / e (%): 614.2 (M + H +, 100).

Example 27

(5RS) -9- (3,5-Bis-trifluoromethyl-benzoyl) -3- (2-morpholin-4-yl-ethyl) -5-phenyl-1-oxa-3,9-diaza-spiro [ 5.5] undecan-2-one

The title compound was obtained in comparable yields following the procedures described for example 23, starting from morpholine instead of pyrrolidine, and 9- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-hydroxy- ethyl) -5-phenyl-1-oxa-3,9-diazaspiro [5.5] undecan-2-one instead of 9- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-hydroxypropyl) - 5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2-one by subsequent treatment with hydrochloric acid in ethanol. ΜΞ m / e (%): 600.1 (M + H +, 100). - 40 -

Example 28

(5RS) -9- (3,5-Bis-trifluoromethyl-benzoyl) -3- (2-dimethylamino-ethyl) -5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan- 2-one

The title compound was obtained in comparable yields following the procedures described for example 23, starting from dimethylamine instead of pyrrolidine, and 9- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-hydroxy ethyl-5-phenyl-1-oxa-3,9-diazaspiro [5.5] undecan-2-one instead of 9- (3,5-his-trifluoromethyl-benzoyl) -3- (3-hydroxypropyl) - 5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2-one by subsequent treatment with hydrochloric acid in ethanol. MS m / e (%): 558.3 (M + H +, 100).

Example 29 (5R) -9- (3,5-Bis-trifluoromethyl-benzoyl) -3- [3- (4-methyl-piperazin-1-yl) -propyl] -5-phenyl-1-oxa- 3,9-diaza-spiro [5. 5] undecan-2-one

The title compound was obtained in comparable yields following the extracts. procedures described for example 23, starting from 4-methyl-piperazine instead of pyrrolidine. MS m / e (%): 627.2 (M + H +, 100). 41

Example 30

[5RS) -9- (3,5-Bis-trifluoromethyl-benzoyl) -5-phenyl-3- (2-pyrrolidin-1-yl) -l-oxa-3,9-diaza-spiro, [5.5] undecan-2-one

The title compound was obtained in comparable yields following the title compound. procedures; described for example 23 starting from 9- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-hydroxy-ethyl) -5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan- 2-one instead of 9- (3,5-bis-trifluoromethylbenzoyl) -3- (3-hydroxy-propyl) -5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2-one, per. treatment with hydrochloric acid in ethanol. MS m / e (%): 584.2 (M + H +, 100).

Example A Ί 1

Tablets of the following composition are manufactured in the usual manner: mg / tablet

Active Substance 5

Lactose 45

Corn starch 15

Microcrystalline cellulose 34

Magnesium stearate 1 100

Tablet Weight 42

Example B

Capsules of the following composition are manufactured: mg / capsule

Active substance 10

Lactose 155

Corn starch 30

Talc _5

Filling weight gives 200 capsule

The active substance, the lactose and the corn starch are first mixed in a blender, and then in a size reduction machine. The mixture is returned to the mixer, the talc is added, and mixed well. The blend is used as a filling of hard gelatin capsules.

Example C

Suppositories are manufactured with the following composition: mg / suppository Active substance 12

Mass of suppositories _1285

Total 1300

The suppository mass is melted in a glass or steel vessel 43, mixed well and cooled to 45 ° C. The active substance is then added, which is very well milled, and is stirred until decanted. it has dispersed completely. The mixture is poured into appropriately sized suppository molds, allowed to cool, the suppositories then withdrawn and individually packed in waxed paper or aluminum foil.

Lisbon, August 13, 2008

Claims (9)

Compounds of the general formula. in which (R1),! is independently in each case halogen, lower alkyl or lower alkoxy; R 2 is hydrogen, lower alkyl, halo-lower alkyl, - (CH 2) m -OH, - (CH 2) m -NR 2, - (CH 2) m O-lower alkyl, - (CH 2) m C - (CH 2) m -heteroaryl having 6 members, optionally substituted with one or more lower alkoxy, - (CH 2) m non-aromatic 5- or 6-membered heterocyclyl, optionally substituted with hydroxy or lower alkyl; R is hydrogen or lower alkyl and may be the same or different in the case of R2; n is 0, 1, or 2; m is 0, 1, 2, 3 or 4; 2 and the pharmaceutically acceptable acid addition salts of these compounds. Compounds of formula I according to claim 1, in which R 2 is hydrogen. Compounds of formula I according to claim 1 which are (5R) -9- (3,5-bis-trifluoromethyl-benzoyl) -5- (3-chloro-phenyl) -1-oxa- (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5- (3,4-difluoro-phenyl) -1-oxa-3 , 9-diazaspiro [5.5] undecan-2-one, (5RS) -9- (3,5-bis-trifluoromethylbenzoyl) -5- (3,4-dichloro-phenyl) -1-oxa-3,9 (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2 (3,5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5- (2,3-difluoro-phenyl) -1-oxa-3,9-diazaspiro [5.5] undecan-2-one , and (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5- (2,5-difluoro-phenyl) -1-oxa-3,9-diazaspiro [5.5] undecan-2-one. Compounds of formula I according to claim 1, in which R 2 is a 6-membered (CH 2) m '3 heteroaryl group, optionally substituted with one or more C 3 -C 7 alkoxy. Compounds of formula I according to claim 4 which are (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -5-phenyl-3-pyridin-3-yl-m, 1-oxa-3,9-diaza-spiro [5.5] undecan-2-one and (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -3- (4,6-dimethoxy- [ 1,3,5] triazin-2-yl) -5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2-one. Compounds of formula I according to claim 1, in which R 2 is a group - (CH 2) m -C (O) -N (CH 3) 2. The compound of formula I according to claim 6 which is (5RS) -2- [9- (3,5-bis-trifluoromethyl-benzoyl) -2-oxo-5-phenyl-1-oxa- 3 ,. 9-diazaspiro [5.5] undec-3-yl] -N, N-dimethylacetamide. Compounds of formula I according to claim 1, in which R 2 is - (CH 2) m OH Compounds of formula I according to claim 8, which are 4 (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-hydroxy-propyl) -5-phenyl (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-hydroxy-ethyl) -piperazin- -5-phenyl-1-oxa-3,9-diazaspiro [5.5] undecan-2-one. Compounds of formula I according to claim 1, in which R 2 is a non-aromatic - (CH 2) m -heterocyclyl group, optionally substituted with hydroxy or lower alkyl. Compounds of formula I according to claim 10 which are (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -3- (1-methyl-piperidin-4-yl) -S- phenyl-1-oxa-3,9-diazaspiro [ 5-undecan-2-one, (5R5) -9- (3,5-bis-trifluoromethylbenzoyl) -5-phenyl-3- (3-pyrrolidin-1-yl-propyl) 9-diazaspiro [5.5] undecan-2-one, (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-morpholin-4-yl-propyl) -5- oxa-3,9-diazaspiro [5.5] undecan-2-one, 5 (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -3- [3- (3-hydroxy-pyrrolidin-1-yl ) -propyl] -5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2-one and (5RS) -9- (3,5-2is-trifluoromethylbenzoyl) -3- (2- morpholin-4-yl-ethyl) -5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2-one. Compounds of formula I according to claim 1, in which R 2 is - (O) m 'NR 2' Compounds of formula I according to claim 12, which are (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -3- (3-dimethylamino-4-yl-propyl) -5- 1-oxo-3,9-diaza-spiro [5.5] undecan-2-one and (5RS) -9- (3,5-bis-trifluoromethyl-benzoyl) -3- (2-dimethylamino-ethyl) -5-phenyl-1-oxa-3,9-diaza-spiro [5.5] undecan-2-one. A medicament containing one or more compounds as claimed in any one of claims 1 to 13 and pharmaceutically acceptable excipients A medicament according to claim 14 for the treatment of diseases related to NK-16 receptor antagonists A process for preparing a compound of formula I as defined in claim 1, which process comprises a) cyclizing a compound of formula in which R 1 has the meanings given above, or b) reacting a compound of formula CF, R 2 -X 7 to give a compound of formula 7 in which R 1 and R 2 have the meanings ascribed to them above and X is halogen, or c) reacting a compound of formula CFa to a compound of formula CF 3, wherein m and R 1 have been described above, or d) reacting a compound of formula 8 with a compound of formula R2NH to a compound of formula wherein the definition of R 1 is shown above, and R 2 is hydrogen or lower alkyl, or e) reacting a compound of formula 9 to a compound of formula in which R 1 is as described above and R 2 " and " R2 " are independently from each other hydrogen, alkyl, aryl, heteroaryl or, taken together, form one. non-aromatic carbocyclic or heterocyclic ring, optionally substituted with halogen, hydroxy, lower alkoxy or hydroxyl or lower alkyl, and if desired converting the obtained compound into a pharmaceutically acceptable acid addition salt thereof. 17. The use of a compound of any one of claims 1-13 for the manufacture of medicaments containing one or more compounds of the formula. I, for the treatment of diseases related to NK-1 receptor antagonists. Lisbon, August 13, 2008